The DOI matches its Crossref record; 37 of the 38 references it cites were found in a registry or an index.
Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones
Open accessAbstract
The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3α-hydroxysteroid dehydrogenase (3α-HSD) isoforms of the aldo-keto reductase (AKR) superfamily. The enzymes correspond to type 1 3α-HSD (AKR1C4), type 2 3α(17β)-HSD (AKR1C3), type 3 3α-HSD (AKR1C2) and 20α(3α)-HSD (AKR1C1), and share at least 84% amino acid sequence identity. All enzymes acted as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductases and as 3α-, 17β- and 20α-hydroxysteroid oxidases. The functional plasticity of these isoforms highlights their ability to modulate the levels of active androgens, oestrogens and progestins. Salient features were that AKR1C4 was the most catalytically efficient, with kcat/Km values for substrates that exceeded those obtained with other isoforms by 10–30-fold. In the reduction direction, all isoforms inactivated 5α-dihydrotestosterone (17β-hydroxy-5α-androstan-3-one; 5α-DHT) to yield 5α-androstane-3α,17β-diol (3α-androstanediol). However, only AKR1C3 reduced ∆4-androstene-3,17-dione to produce significant amounts of testosterone. All isoforms reduced oestrone to 17β-oestradiol, and progesterone to 20α-hydroxy-pregn-4-ene-3,20-dione (20α-hydroxyprogesterone). In the oxidation direction, only AKR1C2 converted 3α-androstanediol to the active hormone 5α-DHT. AKR1C3 and AKR1C4 oxidized testosterone to ∆4-androstene-3,17-dione. All isoforms oxidized 17β-oestradiol to oestrone, and 20α-hydroxy…
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In the citing paper
“17HSD5 may account for much of the extratesticular, peripheral conversion of androstenedione to testosterone, although its catalytic efficiency as a 17HSD is poor (528) compared with its 20␣HSD activity with progesterone and DOC (520) or its prostaglandin dehydrogenase activity, reducing prostaglandin H 2 to prostaglandin F 2␣ (529).”
From The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders (2011) · cites this paper as [528]
In the citing paper
“AKR1C1-AKR1C4 act as 3-keto, 17-keto and 20-ketosteroid reductases to varying extents”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
In the citing paper
“AKR1C enzymes (AKR1C1-AKR1C4) function in vivo as 3-keto-, 17-keto- and 20-ketosteroid reductases to form 3α/β, 17β- and 20α-hydroxy-metabolites to varying extents and thus metabolize a broad spectrum of natural and synthetic therapeutic steroids”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
In the citing paper
“These enzymes are expressed in different tissues, while AKR1C4 is mainly liver specific”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
In the citing paper
“AKR1C1, but also AKR1C2 and AKR1C3 catalyze progesterone reduction to form the less potent progestagen 20α-hydroxy-pregn-4-ene-3-one”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
In the citing paper
“AKR1C3 is the most efficient enzyme for this reaction (KM = 9 μM, kcat = 0.068 mM−1; kcat/KM = 76 min−1 mm−1).”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
In the citing paper
“AKR1C enzymes also act as 17-ketosteroid reductases to reduce the weak estrogen, estrone to form the potent estrogen, 17β-estradiol in peripheral tissues”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
In the citing paper
“Other AKR1C enzymes have much lower activities for 17β-estradiol formation”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [14]
In the citing paper
“AKR1C enzymes are multifunctional and also function as 20α- and 17β-HSDs, with different efficiencies, stereoselectivities and tissue specific expression [104].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [104]
In the citing paper
“the direct 20α-reduction of progesterone terminates its progestogenic activity”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [104]
In the citing paper
“is predominantly catalyzed by AKR1C1 [104,115].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [104]
In the citing paper
“AKR1C1 is the predominant 20-ketosteroid reductase in human [104].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [104]
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Citations
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
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Metadata
- Authors
- PENNING, T. M., BURCZYNSKI, M. E., JEZ, J. M., HUNG, C.-F., LIN, H.-K., MA, H., MOORE, M., PALACKAL, N., & RATNAM, K.
- Affiliations
- University of Pennsylvania (US)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2000-09-26
- Volume
- 351
- Issue
- 1
- Pages
- 67-77
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1221336
- OpenAlex
- W2045040068
- Cited by
- 649
- References
- 38
- Citations by year
- 2026: 21 · 2025: 20 · 2024: 23 · 2023: 15 · 2022: 15 · 2021: 27 · 2020: 19 · 2019: 22 · 2018: 23 · 2017: 18 · 2016: 23 · 2015: 14 · 2014: 47 · 2013: 28 · 2012: 29
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-47015, R01DK047015)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Physical Sciences › Chemistry › Organic Chemistry › Steroid Chemistry and Biochemistry
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- 3α-hydroxysteroid dehydrogenase, aldo-keto reductase superfamily, steroid hormone metabolism, dihydrotestosterone, testosterone, estradiol, progesterone, 20alpha-dihydroprogesterone, 3α-androstanediol, enzyme kinetic parameters, substrate specificity
- MeSH terms
- Androgens, Binding Sites, Catalysis, Cloning, Molecular, Estrogens, Female, Humans, Isoenzymes, Ketones, Kinetics, Male, Organ Specificity, Progestins, Recombinant Proteins, RNA, Messenger, Steroids, Substrate Specificity, 3-Hydroxysteroid Dehydrogenases, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
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